Achondrogenesis

Achondrogenesis (ACG) is a group of severe osteochondrodyplasias  characterised by extremely short limbs, small body and narrow chest, and other skeletal abnormalities. It is a lethal condition, and results in stillbirth or early neonatal death. It is classified into 3 subgroups: type IA (ACGIA, or Houston-Harris type), type IB (ACGIB, or Parenti-Fraccaro type), and type II (ACGII, or Langer-Saldino type). These types are differentiated by their clinical manifestations, histopathological features, and genetic causes (1-3). 

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ACGI is a rare condition, and currently the prevalence is unknown. ACGII occurs in approximately 1:40000-60000 births (4).

ACGIA: 
This is an autosomal recessive condition caused by a mutation in the TRIP11 gene (thyroid hormone receptor interactor 11). This encodes for the Golgi microtubule-binding protein 210 (GMAP-210), which is essential for cellular transport and glycosylation of proteins. This malfunction of the Golgi apparatus occurs within the chondrocytes, which in turn prevents normal cartilage and bone development (3). 

ACGIB:
This is also an autosomal recessive condition, caused by a mutation in the SLC26A2 gene (solute carrier family Homo sapiens 26), located on the long arm of chromosome 5. This causes inactivation of the sulfate-chloride exchanger in the cell membrane, leading to a reduction in intracellular sulfate, and the production of sulfate deplete proteoglycans in the fibroblasts and chondrocytes. This in turn leads to disruption in cartilage formation, endochondral ossification, thereby affecting skeletal growth and formation (2, 5).

ACGII:
This is an autosomal dominant condition, caused by mutations of the COL2A1 gene – also known as the type II collagen gene. This codes for type II collagen - the most abundant protein in the cartilage matrix. These mutations disrupt the process of type II collagen formation and function, thereby interfering with skeletal development and linear growth (6-8). Most of these mutations occur de novo; however, there is evidence of germline mutations which can increase the risk of recurrence (8). Figure 1 summarises the pathogenesis and etiology of the subgroups of ACG.

ACGIA:
The skull is poorly ossified, with no ossification of the vertebral bodies. Multiple fractures are often evident in the ribs. The epiphyseal chondrocytes are hypertrophic and densely packed, with dilated lacunae and presence of intracytoplasmic inclusions. The cartilage matrix, however, appears normal (1, 5).

ACGIB:
The skull is usually mildly affected. The vertebral bodies are either unossified or minimally ossified. Rib fractures are not usually evident. The chondrocytes are loosely arranged in the epiphysis, with collagen rings surrounding the cytoplasm. The cartilage matrix gives the appearance of demasked, coarse collagen fibres (1, 2, 5).

ACGII:
The skull is normally ossified and the vertebral bodies are often less ossified than in ACGIB. Fractures are not usually associated with this type, but the ischial and pubic bones are unossified and the iliac bones hypoplastic. The cartilage matrix is hypercellular and hypervascular, with vacuoles and reduced matrix (swiss cheese appearance) (1, 5). 

ACGIA:
Aside from the extremely short long bones, there is poor ossification in the skull and no ossification in the vertebral bodies (figures 2-5). There are often multiple fractures seen in the ribs and tubular bones. The long bones are rectangular with metaphyseal flare, the neck is short, and the ribs are also short, cupped and flared (1, 3).

ACGIB:
The skull is usually relatively normal, but the vertebral bodies remain minimally ossified. The long bones are shorter than those seen in ACGIA, with no clear axis, and a square or trapezoid appearance. Fractures are less commonly seen. The fingers and toes are extremely short in comparison to the other types of ACG (1, 2). Talipes equinovarus is frequently associated with this type of ACG, and the fetuses are often in breech presentation (5).

ACGII:
The skull is normal and the shortening of the long bones is less severe than in type I. Fractures are not associated with this type, but the ischial and pubic bones are not ossified and the iliac bones are hypoplastic. All 3 types of ACG can be associated with protuberant abdomen, hydrops fetalis and polyhydramnios (1, 7). Figures 6-11 demonstrate a case at 19 weeks’ gestation with a confirmed COL2A1 gene mutation. Figure 12 demonstrates the presence of hydrops fetalis at 23 weeks.

As ACGIA and ACGIB are autosomal recessive conditions, the risk of having another offspring affected with this condition is 25% (4, 5). ACGII is usually caused by a de novo mutation, therefore the risk of recurrence is often <1%. However, if the couple has evidence of germline mutations, the chance of recurrence depends on the percentage of germ cells that are affected with this mutation (4, 8).

Prenatal diagnosis can be achieved through sonographic imaging and molecular genetic testing. In the first trimester, features of short long bones, increased nuchal translucency, abnormally shaped long bones or fractures, hydrops, or under-ossified skull or spine can raise the suspicion of achondrogenesis (9). In the second trimester, the appearance of extremely short long bones, narrow chest, and small body, along with poor ossification, fractures, and abnormal extremities and pelvis, should prompt the suspicion of ACG. Genetic testing to identify mutations in SLC26A2, TRIP11, or the COL2A1 genes can be performed prenatally in the presence of suggestive sonographic features, to facilitate pregnancy and genetic counselling. Histopathological testing of the cartilage and skin biopsies for fibroblast culture can be performed postnatally, or as part of a post-mortem examination, in order to ensure accurate diagnosis and classification (5).

Other lethal skeletal dysplasias can often have similar appearances to ACG. In Thanatophoric dysplasia, the bones are longer, the chest is more elongated, and is often associated with a cloverleaf skull in type 2. Osteogenesis imperfecta is also characterised by under ossification of bones and multiple fractures; the long bones, however, are bowed but not as short. Short-rib polydactyly syndromes include narrow chests, but are usually associated with polydactyly (Figure 13). Robert’s syndrome is associated with severe limb shortening but normal axial bones. Metaphyseal flaring of the long bones is seen in Fibrochondrogenesis, together with clefts of the vertebral bodies (2, 5).

Detailed sonographic assessment, including a full skeletal survey and examination of the extremities, is important in achieving prenatal diagnosis, and to offer management options, including expectant or termination of the pregnancy, at an earlier stage. Invasive testing to identify a mutation in the relevant genes is useful to provide information for prenatal counselling, as well as for future pregnancies.

Diagnosis of ACG is often made following the routine second trimester anomaly scan. However, if there is a family history of skeletal dysplasias, or if the parents have a known carrier status, sonographic screening and invasive testing can be offered early in pregnancy.

ACG is a lethal skeletal dysplasia that often results in stillbirth or early neonatal death secondary to respiratory failure (pulmonary hypoplasia). Figure 14 in the accompanying powerpoint illustrations  demonstrates the X-ray appearances of a fetus with achondrogenesis.

Unfortunately there is currently no treatment available for this condition. Parents with a prenatal diagnosis of ACG can be offered termination of pregnancy, together with counselling by a clinical geneticist. Babies born alive with ACG should be offered palliative care (5).

1.    Kapur RP. Achondrogenesis. Pediatric and Developmental Pathology. 2007;10:253-255
2.    Superti-Furga A. Achondrogenesis type 1B. J Med Genet. 1996;33:957-961
3.    Vanegas S, Fernanda Sua L, López-Tenorio J, Ramírez-Montaño D, Pachajoa H. Achondrogenesis type IA: clinical, histologic, molecular, and prenatal ultrasound diagnosis. The application of clinical genetics. 2018;11:69-73
4.    Achondrogenesis. National Organization for Rare Disorders (NORD). 2017; Available at https://rarediseases.org/rare-diseases/achondrogenesis. Accessed 14/09/2019
5.    Bonafé L, Mittaz-Crettol L, Ballhausen D, Superti-Furga A. GeneReviews 2002. Available at https://www.ncbi.nlm.nih.gov/books/NBK1516/ Accessed 15/09/2019
6.    Körkkö J, Cohn DH, Ala‐Kokko L, Krakow D, Prockop DJ. Widely distributed mutations in the COL2A1 gene produce Achondrogenesis type II/hypochondrogenesis. American Journal of Medical Genetics. 2000; 92:95-100
7.    Chen H, Liu CT, Yang SS. Achondrogenesis: a review with a special consideration of Achondrogenesis type II (Langer-Saldino). American Journal of Medical Genetics. 1981; 10:379-394
8.    Faivre L, Le Merrer M, Douvier S, Laurent N, Thauvin-Robinet C, Rousseau T, Vereecke I, Sagot P, Delezoide AL, Coucke P, Mortier G. Recurrence of Achondrogenesis type II within the same family: evidence for germline mosaicism. American Journal of Medical Genetics. 2004; 126A: 308-312
9.    Khalil A, Paijkrt E, Chitty LS. Early prenatal diagnosis of skeletal anomalies. Prenat Diagn 2011; 31(1):115-24

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